1-[3-, 2-, and 1-indolyl-lower-alkanoyl] piperidines



United. States Patent ful in preparing compounds wherein there is attached to the 1-, 2-, or 3-position of indole through an unsubstituted lower-alkylene bridge interposing from two to six carbon atoms, a l-(piperidyl) group or a l-(lower-alkylatedpiperidyl) group further substituted in the piperidine ring by substituents of a nature to be more fully described hereinafter.

The structural embodiments prepared from compounds of the invention are represented by the formulas I!) (RQn Q 7 n N 3 R4 and are thus represented by the composite formula where any one of the three free valences on the indole ring is taken up by the l-[lower-alkyl]piperidine group and the valences at the 1- and 2-p0sitions when not taken up by the l-[lower-alkyl1-piperidine group are taken up by the groups R and R respectively. In the above general Formulas la, b and c, Alk represents lower-alkylene, R represents from one to two members of the group consisting of hydrogen, hydroxy, halogen, lower-alkoxy, methylenedioxy, lower-alkylmercapto, lower-alkylsulfonyl, and benzyloxy; R represents a member of the group consisting of hydrogen, lower-alkyl, and monocarbocyclic aryllower-alkyl; R represents a member of the group consisting of hydrogen, lower-alkyl, and monocarbocyclic aryl; R4, represents hydrogen or from one to five loweralkyl radicals; R represents a member of the group consisting of hydroxy, hydroxy-lower-alkyl, lower-alkanoyloxy, monocarbocyclic aroyloxy, lower alkanoyloxylower-alkyl, monocarbocyclic aroyloxy-lower-alkyl, cycloalkyl lower alkyl, carbo lower alkoxy, unsubstitutedcarbamyl, N-lower-alkylcarbamyl, N-lower-alkenylcarbamyl, N,N di lower alkylcarbamyl, N-N-di-lower-alkenylcarbarnyl, aminocarbamyl (hydrazido), N-loweralkylaminocarbamyl (N-lower-alkyl-hydrazido .N-loweralkylidenehydrazono, aminoethyl, N lower alkylaminomethyl, N lower alkenylarninomethyl, N,N di loweralkylaminomethyl, N,N di -'lower alkenylaminomethyl, N-lower-alkylamino, N,N-di-lower alkylamino, and N,N- di-lower-alkenylamino; and n represents the integers 1 or 2.

In the above general Formulas la, b, and c, Alk represents lower-alkylene containing from two to seven carbon atoms and interposing from two to six carbon atoms between the indolyl group and the nitrogen atom of the piperidine ring. The loWer-alkylene group can be straight or branched and thus represents, inter alia, 1,2-ethylene 1, 2- (2methy1eth'ylene) -[GH2(.|J H (0 H3) 1,4, butylene [CH CH CH CH 1,3 (l methylpropylene) [CH(CH )CH CH 1,2-(1 ethylethylene) [-CH (C H CH l, 5-pentylene [CH CH CH CH CH 1,4- 3-methylbutylene) [{3I-I CH CH (CH CH 1,4-(2,4-dimethylbutylene) [-CH CH CH CH (CH CH and the like.

In the above general Formulas la, b, and 0, R represents from one to two members of the group consisting of hydrogen, hydroxy, lower-alkoxy, methylenedioxy, lower-alkylmercapto, lower-alkylsulfonyl, or benzyloxy. When R represents two of said groups, the groups may be the same or different and can occupy any of the four available positions on the benzene ring. When R represents lower-alkoxy, lower-alkylmercapto, or loweralkylsulfonyl, the lower-alkylrnoiety of said groups can contain from one to about four carbon atoms and can be either straight or branched. R thus represents, inter alia, methoxy, ethoxy, 2-propoxy, methylmercapto, ethylrnercapto, 2-butylmercapto, methylsulfonyl, ethylsulfonyl, Z-butylsulfonyl, and the like.

In the above general Formulas la, b, and 0, when R or R represent lower-alkyl, the lower-alkyl groupcan contain from one to about four carbon atoms and can be either straight or branched. R and R each thus represent, inter alia, methyl, ethyl, isopropyl, n-butyl, and the like.

When R represents monocarbocyclic aryl or when R represent monocarbocyclic aryl-lower-alkyl, the monocarbocyclic aryl moiety thereof represents phenyl or phenyl substituted by one or more substituents such as, for example, halogen (including fluorine, chlorine, bro mine, and iodine), lower-alkyl, 'hydroxy, lower-alkoxy, methylenedioxy, lower alkylmercapto, lower alkylsulfinyl, lower-alkylsulfonyl, and the like. When the monocarbocyclic aryl moiety is substituted by more than one of the above substituents, the substituents can be the same or difierent and can occupy any of the available positions on the phenyl ring. When the substituent is a lower-alkyl, lower-alkoxy, lower-alkylmercapto, loweralkylsulfinyl, or lower-alkylsulfonyl group, said substituents can be either straight or branched and can contain from one to about four carbon atoms. When R rep resents monocarbocyclic aryl-lower-alkyl, the lower-alkyl part of said group contains from one to two carbon atoms. Thus R represents benzyl or phenethyl and R represents phenyl, or each of such groups substituted in the phenyl ring by one or more of such substituen-ts, inter alia, as fluoro, chloro, bromo, iodo, methyl, isobutyl, hydroxy, methoxy, n-butoxy, methylenedioxy, rnethylrnercapto, isopropylrnercapto, methylsulfinyl, isopropylsulfinyl, methylsulfonyl, isopropylsulfonyl, and the like.

In the general Formulas la, b, and 0, R represents hydrogen or from one to five lower-alkyl radicals. When R represents one or more lower-alkyl radicals, each lower-alkyl radical can contain from one to about four carbon atoms, can be straight or branched and can occupy any of the five available positions on the piperidine ring, and when R represents more than one lower-alkyl radical, said lower-alkyl radicals can be the same or different and can occupy the same or different positions on the piperidine ring. Thus R represents, inter alia, methyl, ethyl, isopropyl, n-butyl, isobutyl, and the like.

When R represents hydroxy, lower-alkanoyloxy, monocarbocyclic aroyloxy, N-lower-alkylamino, N,N-dilower-alkylamino, N,N,-di-lower-alkenylamino, or loweralkanoylamino, said radicals can occupy either the 3- or 4-positions of the piperidine ring. When R represents hydroxy-lower-alkyl, lower alkanoylo-Xy lower alkyl, monocarbocylic aroyloxy lower alkyl, cycloalkyl lower alkyl, carbo lower alkoxy, substituted carbamyl, N lower alkylcarbamyl, N lower alkenylcarbamyl, N,N di lower alkylcarbamyl, N,N di lower alkenylcarbamyl, aminocarbamyl, N lower alkylaminocarbamyl, N lower alkylidenehydrazono, aminomethyl, N lower alkylarninomethyl, N lower alkenylaminomethyl, N,N di lower alkylamino methyl, or N,N di lower alkenylaminornethyl, said radicals can occupy any of the three available positions of the piperidine ring. a

When R represents hydroXy-lower-alkyl, lower-alkanoyloxy lower alkyl, or monocarbocyclic aroyloxy lower alkyl, the hydroxy lower alkyl or oxy low er-alkyl moiety can be straight or branched and can contain from one to about six carbon atoms. R thus stands, inter alia, for hydroxymethyl, 1 hydroXy ethyl, 2 hydroxyethyl, 3 hydroxypropyl, 4 hydroxy butyl, 5 hydroxypentyl, 6 hydroxyhexyl, and the like.

When R represents a lower-alkanoyloxy ester of a hydroxy or hydroXy-lower-alkyl radical, or when R represents a lower-alkanoylamino radical, the loweralkanoyl portion of said radicals can be either straight or branched and can contain from one to about six carbon atoms. R thus also stands, inter alia, for forrnyloxy, 2-formyloxy ethyl, acetoxy, Z-aoetoxy ethyl, propionoxy, Z-propionoxy ethyl, hexanoyloxy, 2-hexanoyloxy ethyl, u-ethylbutryroxy, 2-(a-ethylbutyroxy)ethyl, formylamino, acetylamino, propionylamino, u-ethylbutyrylamino, and the like.

When R represents cycloalkyl-lower-alkyl, the cyclo alkyl moiety contains from five to seven ring carbon atoms, and the lower-alkyl moiety contains from one to two carbon atoms. Thus the cycloalkyl-lower-alkyl radical includes such radicals as cyclopentylmethyl, cyclohexylmethyl, 2-(cyclohexyl)ethyl, cycloheptylrnethyl, and the like.

When R represents a carbo-lower-alkoxy radical, it represents a radical of the formula COOR' Where R is a lower-alkyl group having from one to about six carbon atoms. Thus the carbo-lower-alkoxy radical includes such radicals, inter alia, as carbomethoxy, carboethoxy, carbopropoxy, carboisopropoxy, carbobutoxy, carbohexoxy, and the like.

When R represents a monocarbocyclic aroyloxy or a monocarbocyclic aroyloxy-lower-alkyl radical, the monocarbocyclic aroyl moiety can be benzoyl or benzoyl substituted by one or more substituents selected from the group consisting of halogen (including fluorine, chlorine, bromine, and iodine), lower-alkyl, hydroxy, lower-alkoxy, methylenedioxy, lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, amino, and lower-alkanoylamino. When the monocarbocyclic aroyl moiety is substituted by more than one of the above substituents, the substituents can be the same or different and can occupy any of the available positions on the benzene ring. When the substituent is lower-alkyl, lower-alkoxy, lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, or lower-alkanoylamino, said substituents can be either straight or branched and can contain from one to about four carbon atoms. Thus R also stands, inter alia, for benzoyloxy, 2 (4 fluorobenzoyloxy)ethyl, 2 (2 chlorobenzoyloxy)ethyl, 3 (4 bromobenzoyloxy) propyl, 6 (4 iodobenzoyloxy)hexyl, 3 methylben zoyloxy, 3 (4 isobutylbenzoyloxy) propyl, 4 hydroxy benzoyloxy, 4 methoxybenzoyloxy, 4 n butoxy benzoyloxy, 3,4 methylenedioxybenzoyloxy, 4 methyl rnercaptobenzoyloxy, 4 isopropylmercaptobenzoyloxy, 4 methylsulfinylbenzoyloxy, 4 isopropylsulfinylben zoyloxy, 4 methylsulfonylbenzoyloxy, 4 isopropyl sulfonylbenzoyloxy, 2 (4 aminobenzoyloxy)ethyl, 2 (4 acetylaminobenzoyloxy)ethyl, 3 (3,4 dimethoxy benzoyloxy)propyl, 3 (3 chloro 4 mcthylbenzoyloxy) propyl, and the like.

When R represents N-lower-alkylcarbamyl, N,N-dilower-alkylcarbamyl, N lower alkylaminocarbamyl, N- lower-alkylaminomethyl, N,N di-lower-alkylaminomethyl, N-lower-alkylamino, or N,N-di-lower-alkylamino, the alkyl moiety in each of said radicals can contain from one to about four carbon atoms and can be either straight or branched. Thus R also represents, inter alia, N-methylcarbamyl, N-ethylcarbamyl, N-butylcarbamyl, N,N-dimethylcarbamyl, N,N-diethylcarbamyl, N,N dibutylcarbamyl, N ethylaminocarbamyl, N isopropylaminocarbamyl, N-methylaminomethyl, N-ethylaminomethyl, N- butylaminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N-methylamino, N-ethylamino, N,N- dimethylamino, N,N-diethylamino, or'N,N-dibutylamino.

When R represents N-lower-alkenylcarbamyl, N,N-diloWer-alkenylcarbamyl, N 1ower-alkylidenehydrazono, N-lower-alkenylaminornethyl, N,N di lower alkenylaminomethyl, or N,N-di-lower-alkenylamino, the loweralkenyl or lower-alkylidene moiety of said radicals can contain from three to four carbon atoms and can be straight or branched. Thus R also stands, inter alia, for N-2-propeny1carbamyl, N 2-methy1-2-propenylcarbamyl, N,N-di-(2-propenyl)carbamyl, N,N di (2-methyl-2- propenyl)carbamyl, 2-propylidenehydrazono, N-Z-propenylaminomethyl, N-Z-methyl-Z-propenylaminomethyl, N, N-di-(2-propenyl)aminomethyl, N,N-di-(3-methyl-2-propenyl)aminomethyl, or N,N-dipropenylamino.

The compounds of Formulas Ia, b, and c where R is hydroxy, hydroxy-lower-alkyl, cycloalkyl lower alkyl, aminomethyl, N lower alkylaminomethyl, N-lower-alkenylaminomethyl, N,N-di-lower-alkylaminomethyl, N, N-di-lower-alkenylaminomethyl, N-lower-alkylamino, N, N-di-lower-alkylamino, or N,N-di lower alkenylamino are prepared by reacting with an alkali metal aluminum hydride a respective 1-[(3-indolyl)-lower-alkanoyl]piperidine, 1- (3-indolyl -lower-alkanoyl] -lower-alkylatedpiperidine, 1- [(2-indolyl)-lower-alkanoyl]piperidine, 1- [(2-indolyl)-lower-alkanoyl]-lower-alkylated piperidine, 1-[(l-indolyl)-lower-alkanoy1]piperidine, or 1-[(1-indolyl)-1ower-alkanoyl]-lower alkylated piperidine, which latter have the formulas (1) R4 Allr-ON E (R1) 11 R5 IIa and which are thus represented by the composite formula where any one of the three free valences on the indole ring is taken up by the 1-[lower-alkanoyl]piperidine group and the valences at the 1- and 2-positions, when not taken up by the 1-[lower-alk-anoyl]piperidine group, are taken up by the groups R and R respectively, and Where R R R R and n have the meanings given above, Alk is lower-alkylene containing from one to six carbon atoms and interposing from one to five carbon atoms between the indolyl group and the carbonyl carbon atom of the lower-alkanoyl group, and R is hydroxy, loweralkanoyloxy, monocarbocyclic aroyloxy, hydroxy-loweralkyl, lower-alkanoyloxy lower alkyl, monocarbocyclic aroyloxy-lower-alkyl, cycloallryl lower alkyl, carbolowe-r-alkoxy, tmsubstituted-carbamyl, N-lower-alkylcarbarnyl, N-lower-alkenylcarbamyl, N,N-di-lower-alkylcarbamyl, N,N-di-lower-alkenylcarbamyl, N,N di loweralkylaminomethyl, N,N di lower alkenylaminornethyl, lower-alkanoylamino, N,N-di-lower-alkylamino, or N,N- di-lower-alkenylamino. The reaction is carried out at a temperature in the range of from about 0 C. to about 65 C. in an organic solvent inert under the conditions of the reaction. It is preferred to use lithium aluminum hydride.

The intermediate 3-, 2-, and l-indolyl-lower-alkanoylamides of Formulas Ila, b, and 0 above of the instant invention are prepared by reacting a 3-, 2-, or l-indolyllower-alkanoic acid with a lower-alkyl haloformate in the presence of an acid-acceptor, for example triethylamine, at a temperature between about 20 C. and 20' C. to give a mixed anhydride of a lower-alkyl carbonic acid and the 3-, 2-, or l-indolyl-1ower-alkanoic acid. The latter, have the Formulas V110,, b, and c.

VII!) N Ra l O ll A1k- -0- O-A1kyl VIIc and are thus represented by the composite formula (R1). ll

where any one of the three free valences on the indole ring is taken up by the Alk'--COO-COOA1ky1 group and the valences at the 1- and Z-position, when not taken up by the Alk'-COO-.COOAlkyl group, are taken up by the groups R and R respectively, and where R R R R4,, Alk, and n have the meanings given above and Alkyl represents lower-alkyl containing from one to about five carbon atoms. The reaction is preferably carried out in an organic solvent inert under the conditions of the reaction such as anhydrous acetone, ether, ethylene dichloride, and like. Acetone is the preferred solvent. The purpose of the acid-acceptor is to take up the hydrogen halide split out during the course of the reaction and is a basic substance which forms water-soluble lay-products easily separable from the product.

The indolyl-lower-alkane mixed anhydrides of the (1-, 2- and S-indolyl)-lower-alkanoic acids of Formulas VIIa, b, and 0 thus formed in situ are reacted with an appropriate piperidine or lower-alkylated-piperidine at a temperature between about -20 C. and about 20 C. to give the 1-[ (3-indolyl) -lower-alkanoyl] piperidine, 1- (3-indolyl) lower alkanoyl] lower alkylated piperidine, 1 [(2- indolyl)-loWer-alkanoyl] piperidine, 1-[(2-indolyl) -loweralkanoyl] -lower-alkylated-piperidine, 1-[ 1-indolyl)-loweralkanoyl] piperidine or 1-[ l-indolyl) -lower-alkanoyl] lower-alkylated-piperidine of Formulas Ha, b, and c.

The compounds of Formula Ia where Alk is the 1,2- ethylene group (CH CH R is hydrogen, and R is hydroxy, hydroxy-lower-allryl, cycloalkyl lower alkyl, aminornethyl, N lower alkylaminomethyl, N loweralkenylaminomethyl, N,N di lower-alkylarninomethyl, N,N di lower alkenyl aminomethyl, N- lower -,alkylamino, N,N di loweralkylamino, or N,N-di-loWer-alkenylamino are prepared by reacting with an alkali metal aluminum hydride a respective 1-[(3- indolyl) glyoXalylJpiperidine or l-[(3-indolyl)- glyoxalyl1- lower-alkylated-piperidine which is also within the purview of the instant invention and which has the formula ture in the range from about 0 C. to about 65 C. in an organic solvent inert under the conditions of the reaction. It is preferred to used lithium aluminum hydride.

The intermediate glyoxarnides of formula IIIa are prepared by reacting an indole with a glyoxalyl halide at a temperature in the range from about -20 C. to 25 C. in an organic solvent inert under the conditions of the reaction, such as ether, petroleum ether, dioxane, tetrahydrofuran, and the like thus affording the 3-indolylglyoxalyl halides of Formula Wu. The latter are then reacted with a piperidine or 1ower-alkylated-piperidine of formula V at a temperature in the range from about C. to about 65 C. in the presence of an acid-acceptor to give the 1-[(3-indolyl)-glyoxalyl]piperidines or 1-[(3- indolyl) glyoxalyl]-lower-alkylated-piperidines of Formula IIIa. The reaction is represented by the equation:

IVa V where R R R R and n have the meanings given above, and Hal represents halogen. The reaction is preferably carried out in an organic solvent inert under the conditions of the reaction, for example tetrahydrofuran, ether, ethylene dichloride, and the like. The purpose of the acid-acceptor is to take up the hydrogen halide which is split out during the course of the reaction. The acid-acceptor is a basic substance which forms water-soluble by-products easily separable from the main product of the reaction and includes such substances as alkali metal salts of Weak acids, e.g., sodium carbonate, sodium bicarbonate, potassium carbonate, sodium acetate, and the like. The acid-acceptor can also be in the form of an excess quantity of the piperidine or lower-alkylated-piperidine. A preferred solvent is tetrahydrofuran, and it is preferred to use an excess quantity of the piperidine or lower-alkylated-piperidine as the acid-acceptor.

When R in the compounds of Formulas Ha, b, and c and IIIa is a non-reducible group, for example hydroxy, hydroxy lower alkyl, cycloalkyl-lower-alkyl, N,N-dilower-alkylamino or N,N-di-loWer-alkenylamino, the respective compounds of Formula Ia, b, or c are produoed in which the group R remains unchanged in the reaction. But when R in the compounds of Formulas Ila, b, and c, or Formula HR: is a reducible group, the group R is reduced simultaneously with the alkanoyl carbonyl group or the glyoxalyl group thus producing products of Formulas Ia, b, and c in which the piperidyl group is substituted by the group R in a reduced state. In such cases an additional amount of the alkali metal aluminum hydride must be used in the reaction mixture to insure the complete reduction of both the R substituent and the carbonyl groups of the lower-alkanoyl or glyoxalyl radicals. Thus a one molar equivalent of an alkali metal aluminum hydride, in addition to the one molar equivalent required to reduce the loweralkanoyl carbonyl group or the two molar equivalents required to reduce the glyoxalyl group, would reduce a lower-alkanoyloxy group or a monocarbocyclic aroyloxy group to the hydroxy group, a lower-alkanoyloxy-loweralkyl or a monocarbocyclic aroyloxy-lower-alkyl group to a hydroxy-lower-alkyl group, a carbo-lower-alkoxy group to the hydroxymethyl Le, a hydroxy-lower-alkyl group, the unsubstituted-carbamyl group to the aminomethyl group, an N-lower-alkylcarbamyl group to an N-lower-alkylaminomethyl group, an N-lower-alkenylcarbamyl group to an N-lower-alkenylaminomethyl group, an N,N-di-lower-alkylcarbarnyl group to an N,N- di-lower-alkylaminomethyl group, an N,N-di-lower-alkenylcarbamyl group to an N,N-di-lower-alkenylaminomethyl group, or a lower-alkanoylamino group to an N- lower-alkylamino group.

The compounds of Formulas Ia, b, and c where R is hydroxy, lower-alkanoyloxy, monocarbocyclic aroyl-v oxy, hydroxy-lower-alkyl, lower-alkanoyloxy-lower-alkyl, monocarbocyclic aroyloxy-lower-alkyl, cycloalkyl-lower-alkyl, carbo -lower-alkoxy, unsubstituted-carbamyl,

R n 1) I I VIa, b, e V where R R R R R n, and Alk have the meaning given above and Hal is halogen.

The reaction is preferably carried out in an organic solvent, inert under the conditions of the reaction, for example anhydrous ethanol, benzene, xylene, and the like. The purpose of the acid-acceptor is to take up the hydrogen halide which is split out during the course of the reaction. The acid-acceptor is a basic substance which forms water-soluble by-products easily separable from the main product of the reaction and includes such substances as alkali metal salts of weak acids, e.g., sodium carbonate, sodium bicarbonate, potassium carbonate, sodium acetate, sodium alkoxides, and the like. The acid-acceptor can also be in the form of an excess quantity of the piperidine or lower-alkylated-piperidine.

The compounds of Formula Ia where R is a hydrogen atom and R is hydroxy, hydroxy-lower-alkyl, loweralkanoyloxy, monocarbocyclic aroyloxy, lower-alkanoyloxy-lower-alkyl, monocarbocyclic arolyloxy-lower-alkyl, cycloalkyl-lower-alkyl, unsubstituted-carbamyl, N-loweralkylcarbamyl, N-lower-alkenylcarbamyl, N,N-di-loweralkylcarbamyl, N,N-di-lower-alkenylcarbamyl, N,N-dilower-alkylaminomethyl, N,N di lower alkenylaminomethyl, N,N-di-lower-alkylamino, or N,N-di-lower-alkenylamino are also prepared by reacting phenylhydrazine or an appropriately substituted-phenylhydrazine with a l-(w-formyl-lower-alkyl) substituted piperidine, a l-(wlower-alkanoyl-lower-alkyl)-substituted-piperidine, or a l-(w monocarbocyclic aroyl lower alkyl) substitutedpiperidine. The reaction is represented by the following The reaction, known as the Fischer indole reaction, takes place in two steps with the formation of the hydrazone of Formula VIII occurring in the first step. The hydrazone then rearranges, under the conditions of the reaction, with loss of a molecule of ammonia to form the compounds of Formula Ia.

The reaction is carried out at a temperature in the range from about 20 C. to about 150 C. in an organic solvent inert under the conditions of the reaction, for example, ethanol, methanol, isopropanol, glacial acetic acid, and the like and in the presence of an acid catalyst, for example, sulfuric acid, hydrochloric acid, glacial acetic acid, zinc chloride, cuprous chloride, or boron trifluoride.

The compounds of Formulas Ia, b, and c; Ila, b, and c; and H111 where R is aminocarbamyl (hydrazido) are prepared by reacting the respective compounds of Formulas Ia, b, and Ha, b, and c; and I l-Ia where R is carbo-lower-alkoxy with a molar excess of hydrazine hydrate at a temperature in the range from about 80 C. to about 120 C. Although it is preferred to use 100% hydrazine hydrate, aqueous solutions of hydrazine hydrate can also be used successfully, for example, commercially available 80% solutions.

The compounds of Formulas Ia, b, and 0; Ha, b, and c; and Illa where R is n-lower-alkylidene hydra-Zorro are prepared by reacting the respective compounds of Formulas la, b, and 0; Ha, b, and c; and Illa where R is aminocarbamyl (hydrazido) with a lower-aliphatic aldehyde or di-lcWer-allryl ketone at atemperature in the range from about 50 C. to about 150 C.

The compounds of Formulas la, b, and 0; Ha, b, and c; and Illa Where R is N-lowerall ylami1rocarbamyl are prepared by reducing with hydrogen over a catalyst the respective compounds of Formulas la, b, and c; Ila, b, and c; and Illa where R is'llloWer-alkylidene hydrazono. The reaction is carried out in an organic solvent inert under the conditions of the reaction, for example methanol, ethanol, isopropanol, and the like, at a temperature in the range from about 25 C. to about 75 C. and at hydrogen pressures in the range from about 5040 pounds -p.s.i. A- preferred catalyst is platinum oxide.

The intermediate indolyl-lower-alkyl halides of Formulas Via, b, and 0 used as intermediates in the method described above are prepared by reduction of a l-, 2-, or 3-indolyl-loWer-alkanoic acid lithium aluminum hydride and conversion of the resulting alcohol to the corresponding halide by reacting the former with, for example, a phosphorous trihalide or a thionyl halide.

The compounds of Formulas la, b, and c where R is halide to give a 1-[ (3-, 2-, or l-indolyl)-lower-alkyl]-4- piperidone or lower-al-lrylatedl-piperidone; by reacting a 4-piperidone or lower-allrylatedipiperidone in the presence of an acid-acceptor with a 3-indo-ly-lglyoxalyl halide to give a 1-[ (3-indo-lyl)-glyoxallyl1-4-piperdone or loweralkylatedi-piperidone; or by reacting phenylhydrazine or a sulbstitutedphenylhydrazine with a l-(w-fOhInYl-IGWfiT- alkyl) -4-piperidone, a l-(w-lower-alkanoyl-lower-alkyl) -4- piperidone, or a l-(wnronocarbocyclic aroyl-lower alkyh- 4-piperidone and reacting the product in each case with an alkali metal aluminum hydride to reduce the 4-carbonyl group of the 4-ipiperidone or lower-alkylalted-4- pipenidone ring to the 4-hydroxy group.

Pharmacological evaluation of the compounds of Formulas Ia, b, and c have shown that they possess pharmacodynamic and chemotherapeutic properties, in particular, hypotensive, sedative, anti-inflammatory, monoamine oxidase inhibitory, coronary dilator, adrenolytic, tranquilizing, and antibacterial activities thus indicating their usefulness as blood pressure lowering agents, sedatives, antiinfiammatory agents, psychic energizers, coronary dilators, tranquilizers, and anti-bacterial agents. The compounds of Formulas Ha, b, and c have also been shown to possess hype tensive and coronary dilator activities and are thus useful not only as intermediates in the preparation of the compounds of Formulas In, 12, and 0 but also have utility as blood pressure lowering agents and coronary diiators.

The compounds can be prepared for use by dissolving under sterile conditions a salt form of the compounds in water (or an equivalent amount of a nontoxic acid if the free base is used), or in a physiologically compatible aqueous medium such as saline, and stored in ampoules for intramuscular injection. Alternatively, they can be incorporated in unit dosage form as tablets or capsules for oral administration either alone or in combination with suitable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearate, gum acacia, and the like. Still further the compounds can be formulated for oral administration in aqueous alcohol, glycol or oil solutions or oil-water emulsions in the same manner as conventional medicinal substances are prepared. When used as hypotensive agents, they are formulated and used in the same manner as conventional hypotensive agents, such as reserpine preparations, and indeed can be used advantageously in combination with such hypotensive agents.

The structures of the compounds of the invention are established by their mode of synthesis and corroborated by the correspondence between calculated values for the elements and values found by chemical analysis.

The following examples will further illustrate the invention without the latter being limited thereto.

EXAMPLE 1 3-[2-(4-hydr0ry-1-piperidyl)ethyl] indole [Ia; R R R and R are H, R is 4-OH, Alk is CH CH 1 bromide and 4.5 g. (0.04 mole) of 4-hydroxypiperidine in 200 ml. of acetonitrile was heated under reflux for about twenty hours. The cooled solution was decanted from a viscous yellow oil which had separated, and the oil washed with two 50 ml. portions of acetonitrile. The combined acetonitrile solutions were concentrated in vacuo giving a viscous yellow oil which was dissolved in ml. of 10% aqueous acetic acid. The acid solution was filtered, basified with concentrated ammonium hydroxide, and the solid which separated collected and dried giving 4.55 g. of crude product. The latter, on recrystallization from ethyl acetate, aiiorded 2.37 g. of 3-[2-(4-hydroxy-l-piperidyl)ethyl1indole, M.P. 144.6-l46.8 C. (corn).

3-[2-(4-hydroxy-l-piperidyl)ethyl]indole reacts with formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid, 4-methoxybenzoic acid, phthalic acid, anthranilic acid, l-naphthalenecarboxylic acid, cinnamic acid, cyclohexanecarboxylic acid, mandelic acid, tropic acid, crotonic acid, acetylene dicarboxylic acid, sorbic acid, Z-furancarboxylic acid, cholic acid, pyrenecarboxylic acid, 2-pyridinecarboxylic acid, S-indoleacetic acid, quinic acid, sulfamic acid, methanesulfonic acid, i-sethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid, diethylphosphinic acid, p-aminophenylarsinic acid, phenylstibnic acid, phenylphosphinous acid, methylphosphonic acid, phenylphosphinic acid, Amberlite XE66, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdic acid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid, barbituric acid, boron trifiuoridc, and the like, to give respectively, the formate, acetate, isobutyrate, alphamercaptopropionate, malate (or acid malate), furnarate (or acid fumarate), succinate (or acid succinate), succinamate, tartrate (or bitartrate), citrate (or acid citrate),

1 l lactate, benzoate, 4-methoxybenzoate, phthalate (or acid phthalate), anthranilate, i-naphthalenecarboxylate, cinnamate, eyclohexanecarboxylate, mandelate, tropate, crotonate, acetylene dicarboxylate, sorbate (or acid sorbate), Z-furancarboxylate, cholate, pyrenecarboxylate, Z-pyridinecarboxylate, 3 indoleacetate, quinate, sulfamate, methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, benzenesulfinate, butylarsonate, diethylphosphinate, p-aminophenylarsinate, phenylstibnate, phenylphosphinite, methylphosphonate, phenylphosphinate, Amberlite XE-66 resin salt, hydrofiuoride, hydrochloride, hydrobromide, hydriodide, perchlorate, nitrate, sulfate (or bisulfate), phosphate (or acid phosphate), hydrocyanide,

l2 bromide, benzyl chloride, Z-chlorohenzyl chloride, 2,3,4,5,6-pentachl0robenzyl chloride, or methyl p-toluenesulfonate to give the methiodide, methobromide, ethobromide, allobromide, benzochloride, 2-chlorobenzochloride, 2,3,4,5,G-pentachlorobenzochloride, or metho-p-toluenesulfonate salts, respectively.

The compounds of Formulas Ia and 10 listed in Table 1 below were prepared according to the procedure described above in Example 1 from an appropriate (3- or 1-indolyl)-loweralkyl halide and an appropriate substituted-piperidine. All melting points are corrected unless noted otherwise. The compounds of Formula Ic are indicated by an asterisk TABLE 1 It /A11: Base or salt M .P./cryst. from- 4-OH 230.0235.4 C. CHzCHz isopropanol.

H: 1G0.6-163.2 O. ethyl CHQOHI acetate. Z-CHzOH 10l.4102.2 C. ethyl CHaCHz acetate [hexane 4'CH2OH2OH 116.0118.8 C. ethyl CH2CH2 acetate.

4-OHOHCH3.....--.- 176.8-184.3 O. meth- -.-CH: anol. l-(CHMOH 1e9.4-114.2 C. ethyl CHZCI'IZ acetate. 4-(CH2)4OH 140.6l43.4 O. CH2CH2 acetonitrile. 4-(OHz)5OH 1430-1442 C. CHZOHZ aeetonitrile. 4-(CH1)OH 112.4-115.8 C.ethyl 01120112 acetate. 4-CH1CH2OH 129.2130.4 C. ethyl (OHm acetate/hexane. 4-CHOHCH: l39.8140.8 C. ethyl (011;)3 acetate/hexane. 4-(OH9eO1-I HCl 180.4181.8 C. isopro- (CH2); 13211101. 4-COOCH3 Base 110.4 11l.8 C. acetoue/ CH2CH2 hexane. S-COOC 10 107.8110.4 0. ben- CHZCH: Zeno/hexane. Z-COOC .do 125.2126.8 C. acetone] CHzCHz hexane. 4-COOC HCl 130.6-132A O. meth- (OHm an 3-COOO HCl 116.2ll8.0 C.ethanol/ (C1193 ether. 4-OONH2 Base 182.6-184.0 O. ethyl CHzCHz acetate. 4-NHCOCH3 do 16G.8-l69.2 C. ethyl CHzCHz ace e. 4-OONHCZH5 do 166.4-168.6 O. ethyl OHQCHZ acetate. 4-CON(C2H5)z .do 139.2140.4 O. ethyl CHZCHQ acetate. 4-CONHCH3 -do 139.8-14015" C. ethyl (CHm acetate/hexane. 4-CONHC2H5 do 147.0148.2 C. ethyl CH2 acetate/hexane.

-do 126.8127.8 C. ethyl acetate. 104.2106.0 C. isopropanol. 106.2-10G.8 C. hexane. Da 2-C0NHC1H5 d0 71.273.0 O. ethyl (CH2); acetate/hexane. 4-CHzCeH 1 d0 143.0l43.8 C. hexane. CHZOH;

*Compound 01 Formula 10.

EXAMPLE 30 phosphotungstate, molybdate, phosphomolybdate, pyrophosphate, arsenate, picrate, picrolonate, barbiturate and boron trifluoride salts.

3-[2-(4-hydroxy-1-piperidyl)ethyl]indole can be reacted with hydriodic acid to form 3-[2-(4-hydroxy-1-piperidyl)- ethylJindole hydriodide, useful as a characterizing intermediate.

3-[2-(4-hydroxy-l-piperidyl)ethylJindole, in the form of its hydriodide salt, can be converted to the hydrochloride salt by passing an aqueous solution of the former over an ion-exchange resin saturated with chloride ions, for example Rohm & Haas Amberlite IRA-400 resin.

3-[2-(4-hydroxy-1-piperidyl)ethyl]indole can be reacted with methyl iodide, methyl bromide, ethyl bromide, allyl 3- [2-(4-aminocarbamyl-1-piperidyl) ethyl] indole [Ia; R R R and R are H, R is 4-CONHNH Alk is CH CH A solution of 3.0 g. (0.01 mole) of 3-[2-(4-carbo- The re- The solid 13 which separated was collected, washed with cold hexane and recrystallized repeatedly from a chloroform-hexane mixture giving 3.88 g. of 3-[2-(4-aminocarbamyl-l-piperidyl)ethyl]indole, Ml. 164.6166.0 C. (corn).

EXAMPLE 3 1 3- 2- (4 -ispr0py lidenehydrazo a-l -piperidyl) ethyl] indole [111; R1, R2, R3 and R4 are H, R is 4-CONHN=C(CH3)2,

Alk is 05 0a,]

A solution of 4.0 g. (0.014 mole) of 3-[2-(4-amino carbamyl-l-piperidyl)ethyl]indole in 60 ml. of acetone was heated under reflux for seven hours. The solid that separated from the cooled reaction mixture was collected and recrystallized from ethyl acetate giving 3.27 g. of 3-[2-(4-isopropylidenehydrazono 1 piperidyl)ethyl]indole, IvLP. 184.0186.8 C. (corr.).

EXAMPLE 32 3- [2-(4-is0pwpylaminocarbamyl -piperidyl) ethyl] iizdole [1a, R R R and R are H, R is EXAMPLE 33 3 [2 (2 aminocarhamyl I piperidyDethyl] indole [Ia; R R R and R are H, R is 2-CONHNH All: is CH CH J was prepared from 2.63 g. (0.009 mole) of 3-[2-(2-carbethoxy-l-piperidyl)ethylJindole and 6 ml. of 100% hydrazine hydrate in 50 ml. of isopropyl alcohol according to the manipulative procedure described above in Example 30. The product was recrystallized from a chloroform-hexane mixture giving 1.0 g. of 3 [2-(2 aminocarbamyl-l-piperidyl)ethyl]indole, M.P. 138.4139.8 C. (corn).

EXAMPLE 34 1- [3-(3-hydr0xymcthyl-1-piperidyl)propyl] indole hydrochloride [16; R R and R are H, R is 3-CH OH, Alk is (CH About 15 g. (0.05 mole) 'of 1-[3-(3-carbomethoxy-1- piperidyl)propyl]indole prepared above in Example 18 was dissolved in 250 ml. of dry tetrahydrofuran in a three-necked round bottom flask equipped with a dropping funnel, reflux condenser and mechanical stirrer. To the solution was added with stirring and cooling, a solution containing 2.85 g. (0.08 mole) of lithium aluminum hydride in 250 ml. of anhydrous tetrahydrofuran. When all of the lithium aluminum hydride solution had been added, the mixture was refluxed with stirring for about six hours, and allowed to cool. The excess lithium aluniinum hydride was decomposed by dropwise addition of a solution of 6 ml. of Water in 15 ml. of tetrahydrofuran. The mixture was filtered, the filter cake washed with three ml. portions of tetrahydrofuran, and the combined filtrates were evaporated in vacuo giving a viscous oil. The latter was taken into ether and treated with a solution of anhydrous hydrogen chloride in ether. The precipitated gummy solid was separated from the supernatant liquid by decantation and recrystallized from an isopropanol-ether mixture giving 7.67 g. of 1-[3-(3-hydroxymethyl l-piperidyDpropyl]indole hydrochloride, MP. 127.5l33.3 C. (corn).

EXAMPLE 35 3- [2-(4-ethylamino-I-piperidyl) ethyl] indole dihydrochloride R1, R2, R3 and R4 3T6 H, R5 is 4- IICZHE iS 3-[2-(4-acetylarnino-l-piperidyl)ethyl]indole (7.3 g., 0.03 mole) prepared above in Example 20, in 300 ml. of anhydrous tetrahydrofuran, was reduced with 3.89 g. (0.10 mole) of lithium aluminum hydride in ml. of dry tetrahydroiuran according to the manipulative procedure described above in Example 34. The product was isolated as the free base and converted to the dihydrochloride salt. The latter was recrystallized from an ethanol-ether mixture giving 2.3 g. of 3-[2-(4-ethylamino- 1-piperidyl)ethyl]indole dihydrochloride, MP. 259.6 262 C. (dec.)(corr.).

EXAMPLE 3 6 3-{2-[4-(N ethylaminomethyl) 1 piperidyflethyl} indole dihydrochloride Ha; R R R and R are H, R is 4-CH NHC H Alli is CH CH was prepared from 5.50 g. (0.02 mole) of 3-{2-[4-(N-ethylcarbamyl)-1-piperidyl] ethyl}indole, prepared above in Example 21, by reduction of the latter in 280 ml. of dry tetrahydrofuran with 1.40 g. (0.04 mole) of lithium aluminum hydride in 200 ml. of anhydrous tetrahydrofuran according to the manipulative procedure described above in Example 34. The product was isolated in the form of the free base and converted to the dihydrochloride salt. The latter was recrystallized from a methanol-ether mixture giving 3.18 g. of 3-{2- [4- (N-ethylaminornethyl)-1-piperidy1]ethyl} indole dihydrochloride, does not melt up to 290 C.

EXAMPLES 37-40 By following the manipulative procedure described above in Example 1, substituting for the 2-(3-indolyl) ethyl bromide and the 4-hydroxypiperidine used therein, molar equivalent amounts of an appropriate 6-(3-indolyl) hexyl bromide and an appropriate lower-alkylated piperidine, there can be obtained the compounds of formula Ia listed below in Table 2 where R and R in each case are hydrogen and All; in each case is (CH TABLE 2 (FORMULA Ia) EXAMPLES 4l57 TABLE 3 (FORMULA Ia) Example R HaSCsH4CO EXAMPLE 58 3-{2- [2-(N-allylaminomethyl) -1-piperidyl] ethyl}indle (Ia; R R R and R are H, Alkis (CH R is 2- CH NHCH CH=CH By reacting the 3-{2-[2-(N-allylcarbamyl)-1-piperidyl]- ethyl}indole prepared above in Example 43 with lithium aluminum hydride in an organic solvent inert under the conditions of the reaction, for example diethyl ether or tetrahydrofuran, there can be obtained 3-{2-[2-(N-allylaminomethyl -1-piperidyl] ethyl}indole.

EXAMPLE 59 [1(1; R1, R2, R3 and R4, are H, R5 is 4-(4-NH C H COOCH CH Alli iS CH CH By heating the 3- 2-{4-[2-(4-acetylaminobenzoyloxy)- ethyl-l-piperidyl]ethy1} indole prepared above in Example 54 with concentrated hydrochloric acid and isolating the product from an alkaline medium, there can be obtained 3- 2-{4-[2-(4-aminobenzoyloxy)ethyl-l-piperidyl 1 ethyl} indole.

EXAMPLES 60-76 By following the manipulative procedure described above in Example 1, substituting for the 2-(3-indolyl) ethyl bromide used therein, a molar equivalent amount of an appropriate 2-(3-indolyl)ethyl halide substituted in the 1- and/or 2-positions, there can be obtained the compounds of Formula Ia listed below in Table 4 where 15 R and R4 in each case is hydrogen, R in each case is 4-HO, and Alk in each case is CH CH TABLE 4 (FORMULA Ia) Example EXAMPLE 77 5-chl0r0-2 [2- (4-hydr0xy-J -piperidyl) ethyl] indole [117; R is 5-Cl, R and R are H, Alk is CIIzCHg, and R5 is By reducing 5-chloro-2-indole acetic acid with lithium aluminum hydride in an organic solvent inert under the conditions of the reaction, for example diethyl ether or tetrahydrofuran, there can be obtained S-chloro-Z-(Z- indolyl)ethanol. By reacting the latter with a phosphorous trihalide or a thionyl halide, there can be obtained a 5-chloro-2-(2-indolyl)ethyl halide. By reacting the latter with two molar equivalents of 4-hydroxypiperidine following the manipulative procedure described above in Example 1, there can be obtained 5-chlo1'o-2-[2-(4-hyclroxyl-piperidyl)ethyl]-indole.

EXAMPLE 78 [112; R is 5-CH O, R and R are H, Alk is (CH and R5 is By reacting 5-methoxy-2-(2-indolyl)ethyl bromide with diethylmalonate in the presence of sodium ethoxide and saponifying and decarboxylating the product thus formed in an alkaline medium, there can be obtained 'y-(S-methoxy-2-indo1yl)butyric acid. By reducing the latter with lithium aluminum hydride in an organic solvent inert under the conditions of the reaction, for example diethyl ether or tetrahydrofuran, there can be obtained 4-(5-methoXy-2-indolyl)butyl alcohol. By reacting the latter with a phosphorous trihalide or a thionyl halide, there can be obtained a 4-(S-methoXy-2-indolyl)butyl halide. By reacting the latter with diethylmalonate in the presence of sodium ethoxide and saponifying and decarboxylating the product thus formed in an alkaline medium, there can be obtained e-(5-methoxy-2-indolyl)hexanoic acid which on reduction with lithium aluminum hydride gives 6-(5- methoxy-Z-indolyDhexyl alcohol. By reacting the latter with a phosphorous trihalide or a thionyl halide, there can be obtained a 6-(S-methoxy-Z-indolyl)hexyl halide. By reacting the latter with 4-(2-hydroxyethylpiperidine), there can be obtained 5-methoxy-2-{6-[4-(2-hydroxyeth yl)-l-piperidyl]hexyl}indole.

EXAMPLES 79-82 By following the manipulative procedure described above in Example 1, substituting for the 2-(3-indolyl) ethyl bromide and the 4-hydroxypiperidine used therein, molar equivalent amounts of an appropriate 6-(2-indoly1) 1s EXAMPLE 100 1, and R are H, Alk is CH CH R is 5 hexyl bromide and an appropriate lower-alkylated piperic H COOCH CH dine, there can be obtained the compounds of Formula 2 6 4 2 2)], lb listed. below in Table 5 where R in each case is hydroy reading 2-{4-[2-(4-acetylaminobenzoyloxy) gen and Alk in each case is (CH ethyl-1-piperidyl]ethyl} indole prepared above in Ex- TABLE 5 (FORMULA Ib) Example R1 R Rs 11 79 6-HO 2,4,6-tri-CH 4-HO 1 80.- 5,6-OCHzO 2,2,4,6,6-pcnta-OHa 4-HO 1 s1 -OH3S 2 2-CHzOH2OH- 1 82 6-CHaS0z. 2,2-dl-OH3-6-(CHshCHCHz----. 4-110 1 EXAMPLES 83-98 ample 96 with concentrated hydrochloric acid and isolat- 0 in the product from an alkaline medium there can be By following the manipulative procedure described a above in Example 77, substituting for the 4-hydroxypiperg fi zi g iig idine used therein a molar equivalent amount of an apy y propriately substituted piperidine, there can be obtained E the compounds of Formula Ib listed below in Table 6, XAMPITES 109 where R R and R in each case is hydrogen and Alk in Y ionowmg the pp t pl'ocedure descllbed each Case is (CH2)2 above 1n Example 77, substitutlng for the '5-chloro-2-(2- indoly1)ethyl halide used therein a molar equivalent amount of an appropriate 2-(2-indolyl)ethyl halide sub- 40 stituted in the 1-position, there can be obtained the compounds of Formula 111 listed below in Table 7 where R and R in each case is hydrogen, R in each case is 4-H0, TABLE 6 (TORMULA Ib) and Alk in each case is CH CH H3 ,4-0 CHzOCuHaCOO) R1, R2, and R4, are H, Alk is (CH2) R5 is 2-CH2NHCH2CH=CH2] By reacting the 2-{2-[Z-(N-allylcarbamylPl-piperi dyl]ethy1}indole prepared above in Example 85 with lithium aluminum hydride in an organic solvent inert.

TABLE 7 (FORMULA Ib) Example 2 EXAMPLE 4-hydr0xy-1- [e-(3 inzl0lyl)propionynpiperidine 161; R R R and R are H, R is 4-OH, Alk is CH CH e hours, the triethylamine hydrochloride that had separat The reaction.

The compounds of Formulas Ha and Ho listed below in Table 8 were prepared according to the procedure described above in Example 110 from an appropriate (3- or l-indolyl)-lower-alkanoic acid mixed anhydride and an appropriate substituted-piperidine. All melting points are corrected unless noted otherwise. The compounds of Formula IIc are indicated by an asterisk filtered. The insoluble material was recrystallized from a chloroform-hexane mixture giving 2.53 g. of 4-arnin0- carbamyl 1 [5 (3 indolyl)propionyl]piperidine, M.P. 126.9l30.4 C. (corn).

EXAMPLE 13 6 3- [3-(4-hydr0xy-1-piperidyl) propyl] indole [Ia; R R R R and R are H, R is 4-OH,

A solution of 5.45 g. (0.02 mole) of 4-hydroxy-1-[fl- (3-indolyl)propiony-l]piperidine, prepared above in Example 110, in 270 ml. of dry tetrahydrofuran was treated with a solution of 1.52 g. (0.04 mole) of lithium aluminum hydride in ml. of dry tetrahydrofuran according to the manipulative procedure described above in Example 34. The product was isolated in the form of the free base and recrystallized from an ethyl acetate-hexane mix- TABLE 8 Example Rl/RZ Ra/Rl Rfi/Alk' M.P./Crystd. from- 111 H H 4-C=O 1l9-120 C. (uncorr.).

H 2,6-di-CHa 0112011: ethyl acetate/hexane. 112 4-COOC2H5 123125 O. (uncorr.).

CH2CHz benzene/hexane. 113 4401193011 Brown viscous oil.

OH2CHZ 114 4-(OH940H 2C 2 115 4 (CllfirOH Brown viscous all.

2 2 116 4(01195011 Viscous oil.

20 2 117 4-(CH1).-.OH Dark viscous oil.

2)a 113 4-OOOOH3 91.4-92.8" 0.

CH ethyl acetate/hexane. 119 107-4408 4 C.

ethyl acetate/hexane. 120 86.888.4 O.

. ethyl acetate/hexane. 121 203.6205.2 C.

ethyl acetate/hexane. 122 4-CONHCzH5 l69.5l;71.0 0. (uncorr. CHgCHz ethyl acetate/hexane. 4-CON(C H 133.8-1354? C. CHaCHz ethyl acetate. 4-NHCOOH3 188.8190.2 O. CHzCHg ethanol/hexane. H 4-OH Dark viscous oil. 2.6-di-CH3.- ornom H 4-OH Tan 011. H CHZCH2 H 4-COOCH: Yellow viscous 011. H CHzCHz 12 H 4-CON(CZH )Z Yellow viscous oil.

H CHzCHg 129 H 4-NHCOCH3 127.4128.6 C.

H CHzCHg ethyl acetate. 130 H- 4-CO0CH CH(CHa)2. 107.81O9.2 C.

H CH2 2 ethyl acetate/hexane. 131 H- 3-CONHC2H5 157.4158.4 C.

CHgCHg 132 H 2-C0OCzH5 95.2-97.2 0.

CHzCHa hexane. flfl 133 3-CONHC2H5 111.2-112.8= O.

CH2CHR 1'14 4-COOOH3 1232-1242? C.

CHZCHQ ethyl acetate/hexane.

Compounds of Formula 110 EXAMPLE 135 65 4-amin0carbamyl-1 ,8- (3-ind0lyl propionyl pi peridine [IIa; R R R and R are H, R is 4-CONHNH Alk is (CH A solution of 4.1 g. (0.13 mole) of the 4-carbomethoxy- 1-[fi-(B-indolyl)propionylJpiperidine, prepared above in Example '134, in 12. ml. of 100% hydrazine hydrate and 60 ml. of isopropyl alcohol, was heated under reflux for about seven hours. The mixture was taken to dryness in vacuo, and the resulting solid was slurried with 25 ml. of

ture giving 2.44 g. of 3-[3-(4-hydroxyl-l-piperidyDpropyl]indole, M.P. -l95.2-l98.2 C. (corn). 1

EXAMPLES 137155 The compounds of Formulas Ia and Ic listed below in Table 9 were prepared by reducing the respective compounds of Examples 111-1 29 with lithium aluminum hydride in tetrahydrofuran according to the manipulative procedure described above in Example 34. All melting points are corrected unless noted otherwise. The comsaturated aqueous sodium bicarbonate solution and then 75 pounds of Formula Ic are indicated by an asterisk TABLE 9 Example B1122 B3114 R5/Alk Base or salt M.P./Ct'yst. troni- 137.. H 4-OH Base 198. 2-201. 2 G.

H 2,6-d1-OH3- (011m ethyl acetate/hexane. 138-- H H. 4-CHzOH do 151. 8-153. 2 C.

H l1 (011m ethyl acetate. 139 H H 4-(CH2)aOH do 156. -157. 8 C.

( 2)a ethyl acetate/hexane. 4-(CH2) OH .d0 130. 0-133. 2 C. (CHM ethyl acetate/hexane. 4-(CH2) OH d0 142. 0-143. 4 0.

CH2) a ethyl acetate/hexane. 4-(OHmOH H01 182. 4-184. 6 C.

0112 3 water. 4-(CH93OH Base 140. 2-142. 0 O. HM ethyl acetate/hexane. 4-CH OH do 164. 2-165. 0 C. (CHM ethyl acetate. 3-CH2OH do 160. 8-163. 8 C. (CH2)3 ethyl acetate. 2-CHzOH do 151.4-154. 6 0. m ethyl acetate. 4-CHzNHg 110---. 115. 6-116. 0 C. (CH2)a ethyl acetate/hexane. 4-CH2NHC2H5 21101 245. 4-247. 2 C. 213 ethanol 4-CHzN(CzH5)2 2HC1 202. 4-208 C CHM ethanol. 4'NHG9HK 21101 277. 2-279. 2 C. (CH methanol/ethanol. -OH H01 241.8243.4 C. (0H2): isopropauol/ether.

-OH 90. 0-91. 0 C. OHM benzene/hexane. 4-CH OH -d0 85. 8-87. 0 C. (0132):; ethyl acetate/hexane. 4'CH2N(O2H5)2 2HC1 219. 4-220. 6 C. (CH2); isopropanol/ether. 4-NHC H 2HC1 264. 6-266. 2 C;

(0119 isopropanol/ether.

*Compound of formula 10.

EXAMPLES 156-159 By following the manipulative procedure described above in Example 110, substituting 'for the /3-(3-indolyl)- propionic acid and the 4-hydroxypiperidine used therein, molar equivalent a-mounts of an appropriate e-(3-indolyl)- caproic acid and an appropriate lowcr-alkylated substituted-piperidine, there can be obtained the compounds of Formula Ila listed below in Table 10 where R and R in EXAMPLES 178-194 By following the manipulative procedure described above in Example 110, substituting for the ,8-(3-indolyl) propionic acid used therein a molar equivalent amount of an appropriate fl-(3-indolyl)propionie acid substituted in the =1- and/ or 2-positions, there can be obtained the compounds of Formula IIa listed-below in Table 12 Where R and R in each case is hydrogen, R in each case is each case are hydrogen and Alk in each case is (CH 4 4-HO, and Alk in each case is CH CH TABLE 10 (FORMULA IIa) Example R1 R4 R5 7;

156 6-HO agent-0H3 1 157 56001110..--'2,2,4,6,6-penta-O]E[a 4-H0 1 158 fi-OHQS 5-CzH 1 159 6-CH3SOz 2,2-di-CH3'6'(CH3)2CHGH2... 4110 1 EXAMPLES 1 -177 TABLE 12 (FORMULA Ha) By following the manipulative procedure described above in Example substituting for the 4-hydroxypiperidine used therein a molar equivalent amount of an appropriately substituted piperidine, there can be obtained the compounds of Formula Ila listed below in Table 11 where R R R and R in each case are hydrogen and Alk in each case is (OH J TABLE 11 4 3-CI-IaCuH4C OO) 4-(4-110 CtHaCOO) 4-(4-CH3000H4000) 23 procedure described above in Example 110 and reacting the resulting mixed anhydride with 4-hydroxypiperidine according to the manipulative procedure described above in Example 110, there can be obtained 4-hydroxy-1-[u-(2- indolyl)acetyl]piperidine.

EXAMPLE 196 4-hydroxy-1- [e-'(2-indolyl) hexanoyl] piperidine [IIb; R R and R are H, Alk' is (CH and R is By reacting e-(l-indolynhexanoic acid with isobutyl chloroformate and triethylamine and reacting the resulting mixed anhydride with 41hyd1'oxypiperidine according to the manipulative procedure described above in Example 110, there can be obtained 4-hydroxy-l-[e-(2-indolyl )hexanoyl] piperidine.

EXAMPLES 197-200 By following the manipulative procedure described above in Example 110, substituting for the ,8-(3-ind-olyl) propionic acid and the 4-hydroxypiperidine used therein molar equivalent amounts of an appropriate e-(Z-iIIdOlYl) hexanoic acid and an appropriate lower-alkylated substituted-piperidine, there can be obtained the compounds of Formula IIb listed below in Table 13 where R in each case is hydrogen and Alk in each case is (CH TABLE 13 (FORMULA IIb) 24 Table where R and R in each case is hydrogen, R in each case is 4-HO, and Alk in each case is CH CH TABLE 15 (FORMULA IIb) Example 0 mixture was allowed to stand at about 4 C. for twelve hours. The mixture was filtered and the filtrate evapo- Example R1 R4 R5 11 197 (i-HO 2,4,643ll-CH3 4-HO l 198 5,6-OCHzO 2,2,4,6,6-penta-CHa 4-110 1 199 6-CH3S 5-02 5 2CHzCHiOH- 1 200 6-CHaSOz 2,2-di-CHa-6-(CHa)zCHCH1 4-HO 1 EXAMPLES 201-216 TABLE 14 (FORMULA 110) EXAMPLES 217-225 By following the manipulative procedure described above in Example 110 substituting for the ,(i-(B-indolyl) propionic acid used therein a molar equivalent amount of an appropriate B-(2-indolyl)propionic acid substituted in the l-position of the-indole nucleus, there can be obtained the compounds of formula II!) listed below in rated to dryness in vacuo leaving a reddish oil. The latter was taken into chloroform, washed twice with dilute hydrochloric acid, three times with water, twice with saturated sodium bicarbonate, and three times again with water. The chloroform solution was then dried, taken to dryness in vacuo and the residual red viscous oil was crystallized from an ethyl acetate-hexane mixture giving 10.0 g. of 4-carbomethoxy l (3-indolylglyoxalyl)piperidine, M.P. BSA-136.0" C. (corn).

EXAMPLE 227 3- [2- (4-hydroxymethyl-l -piperidyl) ethyl] indole [111; R1, R2, R3 and R4 are H, R5 is 4'CH2OH,

By reacting the 4-carbomethoxy-1-(3-indolylglyoxalyl)- piperidine, prepared above in Example 226 with lithium aluminum hydride in an organic solvent inert under the conditions of the reaction, for example, tetrahydrofuran, according to the manipulative procedure described above in Example 34, there can be obtained 3-[2-(4-hydroxymethyl-l-piperidyl)ethyl]indole.

EXAMPLES 228-231 Ex. R1 R4 R5 228- -H 2,4,(i-tri-CH: 4-110 229 5,6-OCHzO 2,2 4,6,6-pe11ta-CH3 4-110 230 fi-CHaS 54321 15 Z-CHzCHzOII 231--- 6-CHaSO2 2,2-d1-CH3-6-(CHa)2CI-ICH: 4-110 TABLE 17 (FORMULA 111a) Example R EXAMPLE 255 6-benzyl0xy-t1-[3 (4-hydroxy-1-piperidyl)pr0pyl] indole R is -6-C H OH 0, R and R are 'H, R is 4-OH,

By following the manipulative procedure described above in Example 1, substituting for the 2-(3-indoly1)ethyl bromide used therein a molar equivalent amount of a -3-(6-benzyloxy-1-indoly1)propyl halide, there can be obtained 6 benzyloxy-l-[ 3-(4-hydroxy-d-piperidyl)propyl]- indole.

EXAMPLE 256 4-hydr0xy-1-[B-i(6-benzyl0xy-1-ind0lyl) propionyl] V piperidine [IIc; R is 6-C H CH O, R and R are H, R is 4-OH, Alk' is CH CH By following the manipulative procedure described above in Example 1=10, substituting for the 8-(3-indolyl)-' propionic acid used therein a molar equivalent amount of 3- ('6-benzyloxy41-indolyl)propionic acid, there can be obtained 4-hydroxy-1-[ 8%6-benzyloxy-1-indolyl)propionyl]- piperidine.

EXAMPLE 257 4-carbomethoxy-J4(6-benzyloxy-3-indolylglyoxalyl)- piperidine.

R1 is C6H5CH20, R2, R3 and R4 are H, R5 is 4-COOC H By following the manipulative procedure described above in Example 226, substituting for the 3-indolylglyoxalyl chloride used therein a molar equivalent amount of 6-benzyloxy3-glyoxalyl chloride, there can be obtained 4 carbomethoxy 1 6 benzyloxy-3-indolylglyoxaly1)- piperidine.

EXAMPLE 258 3-{2-[4 (3,4,5-trimethoxybcnzoyloxymethyl)-1- piperidyl] ethyl}indole [141; R R R and R are H, R is 4-[3,4,5(CH O) A solution of 2.5 g. (0.01 mole) of the 3-[2-(4-hydroxymethyM-piperidyl)ethyl] indole, prepared above in Example 3, and 2.5 g. (0.01 mole) of 3,4,5-trimethoxybenzoyl chloride in ml. of acetonitrile was heated under reflux for eighteen hours. The reaction mixture was then taken to dryness. The residue was dissolved in hot water, the solution basified with 10% aqueous sodium bicarbonate solution, and the precipitated solid collected, dried, and recrystallized from methanol giving 2.5 g. of 3-{2- [4-( 3,4, 5 trimethoxybenzoyloxymethyl)-1-piperidyl]ethyl}indole, M.P. 1425-1434 C. (corr.).

EXAMPLE 259 2-mcfhyl-3-{Zv [4 -(2-hydr0xethyl -1 -piperidyl] ethyl}ind0le hydrochloride [Ia; R R and R are H, R is CH R is 4-CH CH OH, Alk is CH CH A mixture of 103 g. (0.8 mole) of 4-(2-hydroxyethyl)- piperidine, 193 g. (1.6 mole) of 1-chloro-4-pentanone and 254 g. (2.4 moles) of anhydrous sodium carbonate in 400 ml. of xylene was heated and stirred on a steam bath for twenty-four hours. The mixture was filtered to remove the precipitated inorganic salts, the filter cake was washed with absolute ether, the washings being combined with the main tilt-rate, and the filtrate evaporated to dryness. Distillation of the residual oil in vacuo gave 117 g. of 1 (3 acetylpropyl)-4-(2-hydroxyethy1)piperidine, B.P. 150-160 C./0.6 mrn.; n -=1.4846.

The 1 (3 acetylpropyl)-4-(Z-hydroxyethyl)piperidine (10.7 g., 0.05 mole) prepared above together with 5.4 g. (0.05 mole) of phenylhydrazine were dissolved in 150 ml. of absolute ethanol containing 15.6 ml. of 6.5 N ethanolic hydrogen chloride. The mixture was refluxed and stirred for twenty-four hours, an additional 7.8 ml. of ethanolic hydrogen chloride being added after the first half hour of refluxing. The mixture was then cooled, filtered, the filter cake slurried with water, filtered again, and washed first with isopropanol then with n-pentane and dried to give 10 g. of 2-methyl-3-{2-[4-(2-hydroxyethyl)- 1 piperidyl]ethyl}-indole hydrochloride, M.P. 256.4- 260.8 C. (corr.).

EXAMPLE 260 2 methyl 5,6 methylenedi0xy-3-{2-[4-(2-hydr0vcyethyl)-1-piperidyl]-efhyl}-ind0le hydrochloride [Ia; R is 5,6-OCH O, R and R are H, R is CH R is 4-CH CH OH, Alk is CH CH was prepared from 9.5 g. (0.05 mole) of 3,4-methylenedioxyphenylhydrazine hydrochloride and 10.7 g. (0.05 mole) of 1-(3-acetylpropyl)-4-(Z-hydroxyethyl)piperidine in ml. of absolute ethanol containing a total of 15.6 ml. of ethanolic hydrogen chloride following the manipulative procedure described above in Example 259. The crude product was purified by slurrying with water, filtering and washing the filter with isopropanol and n-pentane to give 14 g. of 2 methyl-5,6-methylenedioxy-3-{2-[4 (2-hydr0xyethyl) 1 piperidyl]ethyl}indole hydrochloride, M.P. 268.8-2700" C. (corr.).

EXAMPLE 261 1 -{3 [4- (5 -h'ydr0xy pentyl J piperidyl propyl} indole 2,3,4,5,6-pen tachlorobenzochloride [10; R ,.R and R are H, R is 4-(CH OH,

A mixture of 8.74 g. (0.04 mole) of 3-(1-indolyl) propyl chloride, 11.2 g. (0.05 mole) of 4 (5-hydroxypentyl)piperidine hydrochloride, and 10.0 g. (0.12 mole) of sodium bicarbonate in 300 ml. of acetonitrile was refluxed and stirred for forty-eight hours. The reaction mixture was filtered, and the filtrate taken to dryness leaving 13.9 g. of 1-{3-4[-(S-hydroxypentyl)-1-piperidyl] propyl}indole as a yellow viscous oil.

The latter was dissolved in 325 ml. of acetonitrile along with 15.8 g. (0.05 mole) of 2,3,4,5,6-pentachlorobenzyl chloride. The mixture was refluxed for fortyeight hours and the solvent then taken off under reduced pres-sure and the residue caused to crystallize by trituration with ether. The solid' was recrystallized from iso- 27 I propanol to give 2.2 g. of 1-{3-[4-(5-hydroxypentyl)-1- piperidyl]propyl}indole :2,3,4,5,6 pentachlorobenzochloride, M.P. l83.0l84.0 C. (corn).

EXAMPLE 262 1 {3-[4-(3-hydroxypropyl)-1-piperidyl]pr0pyl}ind0le 2,3,4,5,6-pentachlorobenzochloride 10; R R and R are H, R is 4-(CH OH, Alk is (CH was prepared from the 1-{3-[4-(3-hydroxypropyl)-1-piperidyl]propyl} indole prepared above in Example 13, and 2,3,4,5,6-pentachlorobenzyl chloride in acetonitrile according to the manipulative procedure described above in Example 261. The product was recrystallized from isopropanol to give 1-{3-[4-(3-hydroxypropyl) 1 piperidyl]propyl}indole 2,3,4,5,6-pentachlorobenzochloride, M.P. 159.7-163.5 C. (corr.).

EXAMPLE 263 3-{3-[4-(6-hydr0xyhexyl) 1 piperidyl]propyl}indole 2,3,4,5,6-pentachlorobenzochloride [Ia; R R R and R are H, R is 4-(CH OH, Alk is (CH was prepared from the 3-{3-[4-(6-hydroxyhexyl)-1-piperidy]propyl}indole prepared above in Example 142 and 2,3,4,5,6- pentachlorobenzyl chloride in acetonitrile according to the manipulative procedure described abovein Example 261. The product was recrystallized from isopropanol to give 3 {3-[4-(o-hydroxyhexyl)-1-piperidyl]propyl}indole 2,3,4,5,6 pentachlorobenzochloride, M.P. 163.6- 171.2 C. (corn).

The compounds of Formulas Ia, b, and c have been shown to possess hypotensive, sedative, anti-inflammatory, monoamine oxidase inhibitory, coronary dilator, adrenolytic, tranquilizing, and anti-bacterial activities. As representative of these various activities shown by the compounds of the invention are the following:

The minimum effective hypotensive dose (MEHD) of 3-[2-(4-hydroxy-1-piperidyl)ethylJindole, prepared above in Example 1, administered subcutaneously in the renal hypertensive rat, was found to be about 1.0 mg./kg.; the MEHD of 3-[2-(2-hydroxymethyl-l-piperidyl)ethyl1indole, prepared above in Example 4, administered intravenously in the anesthetized dog, was found to be 1.0 mg./kg.; and the MEHD of 3-[2-(4-isopropylidenehydrazono-l-piperidyl)-ethyl]indole, prepared above in EX- ample 31, administered subcutaneously in the renal hypertensive rat, was found to be about 1.0 mg./kg.;

Sedative activity was determined by the potentiation of hexobarbital induced sleeping time in mice. Thus the effective dose, E 50 of 3-{2-[4-(1-hydroxyethyl)-1- piperidyl]ethyl}indole hydrochloride, prepared above in Example 6, in inducing sleep in mice to which 40 mg./kg. of hexobarbital had been administered was found to be 1061465 mg./kg. (oral);

3 [3 -(4-hydroxymethyl-l-piperidyl) propyl] indole, prepared above in Example 138, and 1-[3-(2,6-dimethyl-4- hydroxy-1-piperidyl)propyl]indole hydrochloride, prepared above in Example 151, were found to have antiinfiammatory activity as evidenced by inhibition of dextran edema in rats when administered orally at a dose level of 100 mg./kg./day for three days;

3 [2-(4-isopropylidenehydrazono-1-piperidyl)ethyl]indole, prepared above in Example 31, .1-[3-(4-hydroxymethyl-l-piperidyl)-propyl]indole, prepared above in Example 153, and 3-[2-(4-aminocarbamyl-l-piperidyl)- ethyl]indole, prepared above in Example 30, were found to be about one-tenth as active as iproniazid as a monoamine oxidase inhibiting agent;

3 {3- [4-(3-hydroxypropyl)-1-piperidyl] propyl}indo1e, prepared above in Example 139, was found to produce 7.8% coronary dilatation at a dose level of 0.1 mg./kg. in the isolated rabbit heart;

3-{3-[4-(6-hydroxyhexyl) 1 piperidyl]propyl}indole hydrochloride, prepared above in Example 142, administered intravenously in rats, showed adrenolytic activity as evidenced by antagonism of the pressor effects of epine- 28 phrine. The effective dose, ED in antagonizing epinephrine was found to be 73012161 mcg./kg.;

3 -{2- [4-( 1-hydroxyethyl)-1-piperidyl] ethyl}indo1e hydrochloride, prepared above in Example 6, administered orally produced tranquilization of mice as evidenced by the reaction of the mice to being touched lightly on the vibrissae. The effective dose, ED in producing tranquilization in mice was found to be about 128 mg./kg.;

In standard serial dilution tests, 3-[3-(2,6-dimethyl- 4-hydroxy-1-piperidyl)propyl]indole, prepared above in Example 137, was found to be bacteriostatically effective at a dilution of 122,000 vs. Staph. aureus and Cl. welchii, and about 1: 1,000 vs. E. typhi and Ps. aeruginosa.

The compounds of Formulas IIa, b, and 0 have been shown to possess hypotensive and coronary dilator activities. As representative of these activities shown by the compounds are the following:

The MEHD of 4-aminocarbamyl-l-[B-(3-indolyl)propionyl]piperidine, prepared above in Example 135, administered subcutaneously in the renal hypertensive rat was found to be 1.0 mg./kg.;

4 acetylamino-l-[fi (3-indolyl)propionyl]piperidine, prepared above in Example 124, 4-(N,N-diethy1carbamyl) 1 [fl-(S -indolyl)propionyl]piperidine, prepared above in Example 123, and 4-carbomethoxy-1-[B-(3- indolyl)propionyl]piperidine, prepared above in Example 134, were found to produce 1.6%, 3.1%, and 2.4% coronary dilatation, respectively, at a dose level of 0.1 mg./ kg. in the isolated rabbit heart.

I claim:

1. A compound having the formula Alk'-C O- S 2 where R is carbo-lower-alkoxy of from one to six carbon atoms in the lower-alkoxy moiety and Alk is loweralkylene of from one to six cargon atoms and interposing from one to five carbon atoms between the indolyl group and the carbonyl carbon atom of the lower-alkanoyl group.

2. A compound having the formula where R is N,N-di-lower-alkylcarbamyl and Alk is lower! alkylene of from one to six carbon atoms and interposing from one to five carbon atoms between the indolyl group and the carbonyl carbon atom of the lower-alkanoyl group.

3. A compound having the formula Alk'-C 0 S 2 where R is aminocarbamyl and Alk' is lower-alkylene of from one to six carbon atoms and interposing from one to five carbon atoms between the indolyl group and the carbonyl carbon atom of the lower-alkanoyl group.

4. 4 carbomethoxy 1 [fl (3 indolyl)propionyl] piperidine.

5. 4 (N,N-diethylcarbamyl) 1 [,8 (3 indolyl) propionylJ-piperidine. 6. 4 aminocarbamyl 1 [,8 (3 indolyl)propionyl] piperidine.

29 7. A compound having the formula C -R3 (R1). l l R4 III Alk-CN: R

where any one of the three free valences on the indole ring is taken up by the 1-[lower-alkanoyl]piperidine group and the valences at the 1- and 2-positions, when not taken up by the 1-[lower-.alkanoyl]piperidine group, are taken up by the groups R and R respectively; and where R is a member of the group consisting of hydrogen, hydroxy, halogen, lower-alkoxy, methylenedioxy, lower-alkylrnercapto, lower-alkylsulfonyl, and benzyloxy; R is a member of the group consisting of hydrogen, lower-alkyl, phenyl-lower-alkyl, and Y -phenyl-1ower-a1ky1; R is a member of the group consisting of hydrogen, lower-alkyl, phenyl, and Y -phenyl; R4 is a member of the group consisting of hydrogen and from one to five lower-alkyls each of from one to four carbon atoms; R is a member of the group consisting of hydroxy, hydroxy-loWer-alkyl, loweralkanoyloxy, benzoyloxy, Y -benzoyloxy, lower-alkanoyloxy-lower-alkyl, benzoyloxy-lower alkyl, (Y -benzoy1- oxy)-lower-alkyl, cycloalkyl-lower-alkyl of from five to seven ring carbon atoms, carbo-lower-alkoxy of from one to six carbon atoms in the lower-alkoxy moiety, unsubstituted-carbamyl, N-lower-alkylcarbamyl, N-lower-alkenylcarbamyl of from three to four carbon atoms in the lower-alkenyl moiety, N,N-di-lower-alkylcarbamyl, N,N- di-lower alkenylcarbamyl of from three to four carbon atoms in each lower-alkenyl moiety, aminocarbamyl, N- lower-alkylaminocarbamyl, N-lower-alkylidenehydrazono of from three to four carbon atoms in the lower-alkylidene moiety, N,N-di-lower-alkylaminomethyl, N,N-di-loweralkenylaminomethyl of from three to four carbon atoms in each lower-alkenyl moiety, N,N-di-lower-alkylamino, and N,N-di-lower alkenylamino of from three to four carbon atoms in each lower-alkenyl moiety; Alk' is loweralkylene of from one to six carbon atoms and interposing from one to five carbon atoms between the indolyl group and the carbonyl carbon atom of the lower-alkanoyl group; and n is the integers 1 and 2; and wherein Y is at least one member of the group consisting of halogen, lower-alkyl, hydroxy, lower-alkoxy, methylenedioxy, lower-alkylmercapto, lower-alkylsulfinyl, and lower-alkylsulfonyl; Y is at least one member of the group consisting of halogen, lower-alkyl, hydroxy,1ower-alkoxy, methylenedioxy, lower-alkylmercapto, lower-alkylsulfinyl, and 1oweralkylsulfonyl; Y is at least one member of the group consisting of halogen, lower-alkyl, hydroxy, lower-alkoxy, methylenedioxy, lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, amino, and lower-alkanoylamino; and Y, is at least one member of the group consisting of halogen, lower-alkyl, hydroxy, lower-alkoxy, methylenedioxy, lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsuL fonyl, amino, and lower-alkanoylamino.

References Cited by the Examiner UNITED STATES PATENTS 2,692,882 10/54 Speeter 260--3 19 2,708,197 5/55 Specter 2603 19 2,769,818 11/5'6 Schlesinger 260294 2,857,390 10/58 Kirchner 260294 3,000,885 9/61 Cusic 260294 X 3,007,93 3 11/61 Hennion 260293 3,007,934 11/61 Bencze 260294.7 X 3,014,037 12/61 Rorig 260294.7 3,036,081 5/ 62 Nomine et a1 260294.7 3,072,530 1/63 Hofmann et al 260294.7 X 3,075,976 1/ 63 Jacob et a1. 260294.7 X $75,986 1/ 63 Jacob et a1. 260294.7

OTHER REFERENCES James R. Vaughan, Jr.: J. Am. Chem. Society, vol. :73, page 3547 (1957).

NICHOLAS S. RIZZO, Primary Examiner.

I. MARCUS, Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,183,235 May 11, 1965 Bernard L. Zenitz It is hereby certified that error appears in the above numbered pat ent requiring correction and that the said Letters Patent should read as corrected below.

In the heading to the printed specification, lines 2 and 3, title of invention, for "l-[3-, 2-, and l-INDOLYL-LOWER- ALKANOYL]PIPERIDINES" read 1- [(3, 2- and l-INDOLYL) LOWER-ALKANOYL]PIPERIDINES column 2, line 9, for "aminoethyl" read aminomethyl line 30, for "[CH CH CH (CH )CH read [-CH CH CH(CH )CH column 6, line 38, for

"l-[l-indolyl)-" read l-[[1-indoly1)- column 9, line 57, for "glyoxally] 4-piperdone" read glyoxalyl] 4-piperidone column 10, line 34, after "CH CH insert A solution of 4.48 g. (0.02 mole) of 2(3-indo1y1)ethyl as the beginning of a new paragraph; column 15, TABLE 3, second column, line 6, thereof for "2- (2-ClC H COOCH CH read 2- (2-C1C H 6 4 6 4 COOCH CH J column 26, line 11, for "(2hydroxethyl)-", in italics, read -(2hydroxyethyl) in italics; line 68, for "1-{3-4[-(5" read 1{3[4(S column 28, line 42, for "cargon" read carbon Signed and sealed this 16th day of November 1965.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

6. 4 - AMINOCARBAMYL - 1 - (B-(3 - INDOLYL) PROPIONYL) PIPERIDINE.
 7. A COMPOUND HAVING THE FORMULA 